Chronic pain due to various health conditions remains a common clinical problem affecting millions of people worldwide. Opioid therapies are still most effective for control of chronic pain and have been increasingly used clinically for desired and sustained pain relief. However, beside analgesic effects, opioids also have strong rewarding effects and highly addicting properties after repeated use, leading to opioid dependence and addition. In fact, there have been increased case reports of non-medical opioid misuse, abuse and incidences of opioid addiction among chronic pain patients under a long-term opioid therapy. This trend is significantly weighing on physicians' decisions on prescribing opioids of long-term, thus limiting the optimal use of opioid analgesics for maximum pain control. Nevertheless, little is known currently about how an existing pain would change the reinforcing and addicting properties and consequently abuse potential of opioids through their functional interactions. Focusing on neurons in the central amygdala, a brain area increasingly recognized as crucial for emotional modulation of both chronic pain and drug addiction, this project is aimed to identify synaptic adaptations specifically induced by chronic pain and by a rewarding opioid, and to determine how chronic pain- induced changes affect the rewarding properties and resultant abuse potential of opioid analgesics used for pain control through interacting adaptations on the key glutamate neurotransmission. Two common rat models of chronic pain will be used: rats with complete Freund's adjuvant-induced persistent inflammatory pain and rats with spinal nerve ligation-induced prolonged neuropathic pain. The behavioral measure of opioid reward and addiction will be achieved by using two commonly used rat models: opioid-induced conditioned place preference and opioid self-administration. Our preliminary studies in these rat models have revealed important and interesting data, which indicate that chronic pain may induce similar synaptic adaptations to those induced by repeated opioids in amygdala neurons and facilitate the reinforcing effects of opioids and related behaviors. Based on these preliminary findings, our central hypothesis is that chronic pain facilitates synaptic adaptations induced by rewarding opioids through glutamate neurotransmission, exacerbating opioid-seeking and intake behaviors. To test this hypothesis, this project will employ multidisciplinary approaches to determine the impact of chronic pain on opioid addiction and underlying synaptic mechanisms in the amygdala at cellular, molecular and behavioral levels. It is traditionally believed that pain would serve as a negative emotional stimulus against the rewarding properties of opioids, but supporting experimental evidence is lacking. Therefore, this project is expected to provide conceptually new information regarding the functional interactions between chronic pain and opioid reward. Findings of this project will help to identify pharmacological targets for the development of new opioid therapies that minimize abuse potential of opioid analgesics while maximizing their analgesic effects. PUBLIC HEALTH RELEVANCE: Chronic pain, a common health condition affecting millions of people, requires long-term use of opioids, the most effective analgesics currently available, for efficient and sustained pain control. However, repeated use of opioids causes drug dependence and sometimes addiction, characterized by compulsive behaviors of drug misuse and abuse, due to the strong reinforcing effects of opioids. This project investigates how an existing pain condition changes the reinforcing effects of opioids and consequently the risk of developing behaviors of opioid misuse and addiction. The goal of this project is to identify pharmacological targets to reduce the abuse potential of opioids taken for pain control while maintaining their analgesic effects.